There is a tremendous amount of variation in brain structure and function. This natural variation has important health consequences. Individual variation contributes to adverse drug reactions, dangerous variation in response to general anesthetics, and inappropriate and ineffective drug dosages. We know almost nothing about the underlying neuroendocrine and genetic bases of variation in brain pathways, nor do we have anything more than an empirical sense of how to deal with brain variation as a public health issue. This proposal investigates variation in a neuroendocrine pathway. The research will be conducted on a neuroendocrine pathway that is both intensively studied and known to contain high levels of genetically based individual variation, the pathway through which the short photoperiods cause changes in alter [sic] reproduction, body weight, the immune system, and behavior as adjustments to winter. In humans, elements of this neuroendocrine pathway are thought to play a role both in reproduction and in some types of depression. Preliminary work has identified photoperiod-dependent differences in reproduction, food intake, and body weight among the F344, BN and Harlan Sprague Dawley strains of rats. In addition, preliminary results indicate that the most commonly studied inbred rat strain (F344) and perhaps another strain that is extremely important in biomedical research (BN) undergo hitherto unknown physiological changes in commonly-used laboratory photoperiods, and that these effects could cause spurious results in many research studies. The specific aims of this project are to test how differences in the brain and its chemical messengers cause these changes in fertility and body weight. The project will test whether differences in circadian rhythms (the biological clock) and/or the way in which rats secrete or respond to the hormone melatonin cause these differences in fertility and body weight. These studies will allow us to link variation in phenotype to an underlying neuroendocrine cause. They will begin to uncover the basis for this variation in the brain, and they will provide us with information on the kind of variation we can expect to find in brain pathways. Finally, this work will help us develop ways to understanding the extent and significance of individual variation in the brain in mammalian populations, including human populations.